HDAC inhibitors induce cell cycle arrest, activate the apoptotic extrinsic pathway and synergize with a novel PIM inhibitor in Hodgkin lymphoma‐derived cell lines

Martín-Sánchez, Esperanza; Sánchez‐Beato, Margarita; Rodríguez, Maria E.; Sánchez-Espiridión, Beatriz; Gómez-Abad, Cristina; Bischoff, James R.; Piris, Miguel Á.; Garcı́a-Orad, Africa; Garcı́a, Juan F.

doi:10.1111/j.1365-2141.2010.08401.x

Cited by 10 publications

(7 citation statements)

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“…For this reason, it might be worthwhile exploring drug combinations targeting downstream effectors of the oncogenic-driver ALK translocation. Additionally, PIMi are known to synergize strongly with other antitumoral agents, such as Cisplatin, as demonstrated here in PTCL, the MEK inhibitor UO126 in precursor T cell lymphoblastic leukemia [29], the PI3 K inhibitor GDC-0941 in acute myeloid leukemia [21], the HDAC inhibitor SAHA in classical Hodgkin lymphoma [42], Bendamustine in mantle cell lymphoma and splenic marginal zone lymphoma [43], the BCL2 inhibitor ABT-737 [44] and taxanes [45] in prostate cancer and the multi-kinase inhibitor Sunitinib in renal cell carcinoma [46].…”

Section: Discussionmentioning

confidence: 80%

PIM Kinases as Potential Therapeutic Targets in a Subset of Peripheral T Cell Lymphoma Cases

et al. 2014

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Currently, there is no efficient therapy for patients with peripheral T cell lymphoma (PTCL). The Proviral Integration site of Moloney murine leukemia virus (PIM) kinases are important mediators of cell survival. We aimed to determine the therapeutic value of PIM kinases because they are overexpressed in PTCL patients, T cell lines and primary tumoral T cells. PIM kinases were inhibited genetically (using small interfering and short hairpin RNAs) and pharmacologically (mainly with the pan-PIM inhibitor (PIMi) ETP-39010) in a panel of 8 PTCL cell lines. Effects on cell viability, apoptosis, cell cycle, key proteins and gene expression were evaluated. Individual inhibition of each of the PIM genes did not affect PTCL cell survival, partially because of a compensatory mechanism among the three PIM genes. In contrast, pharmacological inhibition of all PIM kinases strongly induced apoptosis in all PTCL cell lines, without cell cycle arrest, in part through the induction of DNA damage. Therefore, pan-PIMi synergized with Cisplatin. Importantly, pharmacological inhibition of PIM reduced primary tumoral T cell viability without affecting normal T cells ex vivo. Since anaplastic large cell lymphoma (ALK+ ALCL) cell lines were the most sensitive to the pan-PIMi, we tested the simultaneous inhibition of ALK and PIM kinases and found a strong synergistic effect in ALK+ ALCL cell lines. Our findings suggest that PIM kinase inhibition could be of therapeutic value in a subset of PTCL, especially when combined with ALK inhibitors, and might be clinically beneficial in ALK+ ALCL.

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Section: Discussionmentioning

confidence: 80%

PIM Kinases as Potential Therapeutic Targets in a Subset of Peripheral T Cell Lymphoma Cases

et al. 2014

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“…Furthermore, because both the PTEN/PI3K and JAK/STAT pathways converge on the regulation of many signaling proteins that are common to both the AKT and PIM families, it is possible that some redundancy between these pathways also occurs in tumors. In fact, it has been reported that PIM inhibitors synergize with mTOR or PI3K inhibitors …”

Section: Discussionmentioning

confidence: 99%

“…In fact, it has been reported that PIM inhibitors synergize with mTOR or PI3K inhibitors. 89,148,158,165…”

Section: Discussionmentioning

confidence: 99%

“…PIM inhibitors also recovered the sensitivity to many chemotherapeutic drugs in resistant cell lines . In vivo, most PIM inhibitors are more active against tumor xenografts when used in combination with classical or novel‐targeted therapies …”

Section: Pim Inhibitorsmentioning

confidence: 99%

“…123 In vivo, most PIM inhibitors are more active against tumor xenografts when used in combination with classical or novel-targeted therapies. [163][164][165] Remarkably, a combination of PIM inhibitors with EGFR inhibitors or PI3K/mTOR inhibitors displays a strong synergism in in vivo models. 149,166 Finally, PIM inhibitors could also block the migration and invasion of solid tumor cells.…”

Section: Pim Inhibitorsmentioning

confidence: 99%

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The PIM Family of Serine/Threonine Kinases in Cancer

Narlik-Grassow

Blanco‐Aparicio

Carnero

2013

Medicinal Research Reviews

196

192

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The proviral insertion site in Moloney murine leukemia virus, or PIM proteins, are a family of serine/threonine kinases composed of three different isoforms (PIM1, PIM2, and PIM3) that are highly evolutionarily conserved. These proteins are regulated primarily by transcription and stability through pathways that are controlled by Janus kinase/Signal transducer and activator of transcription, JAK/STAT, transcription factors. The PIM family proteins have been found to be overexpressed in hematological malignancies and solid tumors, and their roles in these tumors were confirmed in mouse tumor models. Furthermore, the PIM family proteins have been implicated in the regulation of apoptosis, metabolism, cell cycle, and homing and migration, which has led to the postulation of these proteins as interesting targets for anticancer drug discovery. In the present work, we review the importance of PIM kinases in tumor growth and as drug targets.

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Down‐Regulation of Thioredoxin1 Is Involved in Death of Calu‐6 Lung Cancer Cells Treated With Suberoyl Bishydroxamic Acid

You

Park

2015

J of Cellular Biochemistry

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Suberoyl bishydroxamic acid (SBHA), a histone deacetylase (HDAC) inhibitor, can show an anticancer effect. In this study, we investigated the effects of SBHA on the growth inhibition and death of Calu-6 and NCI-H1299 cells in relation to reactive oxygen species (ROS) and antioxidant levels. SBHA inhibited the growth of Calu-6 and NCI-H1299 lung cancer cells with an IC50 of 50 µM at 72 h. This agent induced apoptosis in Calu-6 cells and triggered to a G2/M phase arrest in NCI-H1299 cells. Although it also reduced the growth of normal human pulmonary fibroblast (HPF) cells, the susceptibility of Calu-6 cells to SBHA was higher than that of HPF cells. In addition, SBHA did not affect the growth of human small airway epithelial cells (HSAEC). Regarding ROS and antioxidant levels, SBHA increased ROS level and glutathione (GSH) depletion in Calu-6 and NCI-H1299 cells whereas it decreased ROS levels in HPF and HSAEC. SBHA also decreased thioredoxin1 (Trx1) level in Calu-6 cells. Although the down-regulation of Trx1 intensified apoptosis and ROS level in SBHA-treated Calu-6 cells, the overexpression of Trx1 attenuated apoptosis and ROS level in these cells. This down-regulation of Trx1 did not affect apoptosis-signaling regulating kinase1 (ASK1) activation. In conclusion, the down-regulation of Trx1 by SBHA was closely involved in cell death in Calu-6 cells.

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HDAC inhibitors induce cell cycle arrest, activate the apoptotic extrinsic pathway and synergize with a novel PIM inhibitor in Hodgkin lymphoma‐derived cell lines

Cited by 10 publications

References 11 publications

PIM Kinases as Potential Therapeutic Targets in a Subset of Peripheral T Cell Lymphoma Cases

PIM Kinases as Potential Therapeutic Targets in a Subset of Peripheral T Cell Lymphoma Cases

The PIM Family of Serine/Threonine Kinases in Cancer

Down‐Regulation of Thioredoxin1 Is Involved in Death of Calu‐6 Lung Cancer Cells Treated With Suberoyl Bishydroxamic Acid

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